Zonisamide (CI-912) and Cognition: Results from Preliminary Study

Nine patients with refractory partial seizures were evaluated in a pilot study of a new anticonvulsant compound, zonisamide (l,2-benzisoxazole-3-methane-sulfonamide; CI-912). Cognitive functioning was evaluated prior to treatment with zonisamide and repeated after 12 and 24 weeks of treatment with zonisamide. At minimum steady-state plasma concentrations >30 jjug/ml, zonisamide appeared to affect specific cognitive functions such as acquisition and consolidation of new information. Previously learned material, such as vocabulary, and psychomotor performance were not affected. Verbal learning was affected, while visual-perceptual learning was unimpaired. These cognitive effects were observed in the absence of the usual clinical signs and symptoms of toxicity. A linear relationship was found between impairment of cognitive abilities and the minimum plasma concentration (r = -0.73; p < 0.05). Findings also suggest the development of tolerance to the adverse cognitive effects. RESUMEN En un estudio piloto realizado para valorar la eficacia de la zonisamida (1,2-Bencisoxazol-melanosulfonamida [CI-912]), un nuevo compuesto anticonvulsive se han evaluado unos 9 pa-cientes con ataques parciales refractarios al tratamiento. Se de-terminÓ la capacidad cognitiva anterior al tratamiento y se re-pitio 12 y 24 semanas despuÉs del tratamiento con zonisamida. Con concentraciones plasmÁticas mÍnimas estables per encima de 30 mcg/ml, la zonisamida afectÓ las funciones cognitives especÍficas tales como la adquisiciÓn y consolidaciÓn de nueva informaciÓn. El material aprendido previamente, tal como el vo-cabulario, y las funciones psicomotoras no se afectaron. El aprendizaje verbal se modificÓ mientras que el aprendizaje visuo-perfectivo no se modificÓ. Estos efectos cognitivos se ob-servaron en ausencia de los habituales signos y sÍntomas clÍnicos de toxicidad. Se encontrÓ una relaciÓn lineal entre la alteraciÓn de las posibilidades cognitivas y la concentraciÓn plasmÁtica mÍnima (r = -0.73, p < 0.05). Estos hallazgos tambiÉn sugieren el desarrollo de una tolerancia a los efectos cognitivos adversos. ZUSAMMENFASSUNG 9 Patienten mit rezidivierenden Partial-AnfÄllen wurden in einer Pilotstudie mit einer neuen antiepileptischen Substanz: Zonisamide untersucht. Die kognitiven Funktionen wurden vor der Behandlung mit Zonisamide geprtÜft und nach 12 und 24 Therapiewochen mit Zonisamide wiederholt. Bei einem Min-destplasmaspiegel von 30 mcg/ml schien Zonisamide spezifische kognitive FÄhigkeiten wie Aufnahme und Speicherung neuer In-formationen zu beeintrÄchtigen. Vorher gelernte Inhalte wie sprachliche und psychomotorische Fertigkeiten wurden nicht beeinflußt. Verbales Lernen war ebenfalls betroffen, wÄhrend visuell, perzeptives Lernen nicht verschlechtert war. Diese BeeintrÄchtigung kognitiver Funktionen wurde bei fehlenden klinischen Intoxikationszeichen beobachtet. Eine lineare Bezie-hung zwischen Verschlechterung kognitiver FÄhigkeiten und Mindest-Plasmaspiegel konnte hergestellt werden (r = -0,73; p < 0,05). Allerdings lassen die Ergebnisse auch auf eine GewÖhnung an diese unerwÜnschten Nebenwirkungen schließen.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65995/1/j.1528-1157.1987.tb03624.x.pd

Pilot Study of Zonisamide (1,2-Benzisoxazole-3-methanesulfonamide) in Patients with Refractory Partial Seizures

A new anticonvulsant compound, zonisamide (1,2 benzioxazole-methanesulfonamide), was studied in 10 adults with medically refractory partial seizures. Following a single oral dose of 400 mg, peak plasma levels occurred an average of 2.8 h after dosing, and the mean clearance from plasma was 2.34 L/h. Whole blood concentrations were high than plasma concentrations because of red blood cell binding. steady-state plasma concentrations were high than predicted from a linear kinetic model. In most patients, seizure frequency was reduced after zonisamide was substituted for a standard antiepileptic drug. Dose-related reversible side effects in the central nervous and gastrointestinal system were observed. Most patients tolerated doses between 5.2 and 12.5 mg/kg/day. RÉSUMÉ Un nouveau produit anticonvulsivant, le zonisamide (1,2 benziosoxazole-methylsulfonamide) a ÉtÉ administrÉÀ 10 adultes atteints de crises partielles non contrÔlÉes par le traitement mÉdical. AprÈs une dose unique orale de 400 mg, le pic du taux plasmatique survient en moyenne 2 h 1/2 aprÉs l'ingestion, et la clairance plasmatique moyenne est de 2,34 litres par heure. les concentrations sanguines totales sont plus ÉlevÉes que les concentrations plasmatiques, en raison de la liaison aux globules rouges, les concentrations plasmatiques À l'État d'equilibre sont plus ÉlevÉes que celles que l'on peut dÉdurie d'un modÈle de cinÉtique linÉaire. Chez la plupart des patients, la frÉquence des crises a ÉtÉrÉduite par la substitution du zonisamide au traitement antiÉpileptique standard. Des effets secondaires doses-dÉpendants et rÉversibles ont ÉtÉ observÉs au niveau du systÈme nerveux central et du tube digestif. La plupart des patients ont tolÉrÉ des doses entre 5,2 et 12,5 mg/kg de poids par jour. RESUMEN En 10 adultos con ataques parciales refractarios a1 tratamiento mÉdico, se ha estudiado la acciÓn de un nuevo compuesto anticonvulsivo, la zonisamida (1,2 benzisoxazol-metanosulfonamida). Tras la ingestiÓn de una sola dosis oral de 400 mg., se alcanzaron los niveles pico en plasma en un promedio de 2.8 horas desputs de la dosis y el aclaramiento medio del plasma fuÉ de 2, 34 litros/hora. Las concentraciones en sangre fueron mÁs altas que las plasmÁticas debido a que la medicaciÓn se ligaba a los hematies. Las concentraciones plasmÁticas estables fueron mÁs altas que las previsibles de un modelo cinÉtico lineal. En la mayorÍa de los pacientes la frecuencia de los ataques se redujo despuÉs de cambiar la medicaciÓn antiepilÉptica standard por la zonisamida. TambiÉn se observaron los efectos colaterales sobre el tracto gastrointestinal y el sistema nervioso central que estaban relacionadas con la dosis y eran reversibles. La mayor parte de los pacientes tolerÓ dosis que oscilaban entre 5.2 y 12.5 mg/kg/dÍa. ZUSAMMENFASSUNG Ein neues Antikonvulsivum, Zonisamid (1,2 Benzisoxazol-Methansulfonamid) wurde bei 10 Envachsenen mit therapieresistenten PartialanfÄllen gesucht. Nach einer oralen Einzeldosis von 400 mg wurden Plasmaspitzenwerte im Durchschnitt nach 2, 8 Stunden erreicht. Die mittlere Clearance aus dem Plasma betrug 2, 34 L/Stunde. Ganzblutkonzentrationen waren hÖher als Plasmakonzentrationen aufgrund der Bindung an die roten BlutkÖrperchen. Die steady-state Plasmakonzentrationen waren hÖher als bei einem linearen kinetischen Modell zu envarten. Bei den meisten Patienten konnte die Anfallsfrequenz nach Substitution eines Standardantiepileptikums durch Zonisamid reduziert werden. Es bestanden dosisabhÄngige, reversible, zentral-nervÖse und gastrointestinale Nebenwirkungen. Die meisten Patienten tolerierten Dosen zwischen 5, 2 und 12, 5 mg/kg/Tag.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65938/1/j.1528-1157.1985.tb05407.x.pd

Moment inversion problem for piecewise D-finite functions

We consider the problem of exact reconstruction of univariate functions with jump discontinuities at unknown positions from their moments. These functions are assumed to satisfy an a priori unknown linear homogeneous differential equation with polynomial coefficients on each continuity interval. Therefore, they may be specified by a finite amount of information. This reconstruction problem has practical importance in Signal Processing and other applications. It is somewhat of a ``folklore'' that the sequence of the moments of such ``piecewise D-finite''functions satisfies a linear recurrence relation of bounded order and degree. We derive this recurrence relation explicitly. It turns out that the coefficients of the differential operator which annihilates every piece of the function, as well as the locations of the discontinuities, appear in this recurrence in a precisely controlled manner. This leads to the formulation of a generic algorithm for reconstructing a piecewise D-finite function from its moments. We investigate the conditions for solvability of the resulting linear systems in the general case, as well as analyze a few particular examples. We provide results of numerical simulations for several types of signals, which test the sensitivity of the proposed algorithm to noise

Complex Wavelets for Extended Depth-of-Field: A New Method for the Fusion of Multichannel Microscopy Images

Microscopy imaging often suffers from limited depth-of-field. However, the specimen can be “optically sectioned” by moving the object along the optical axis. Then different areas appear in focus in different images. Extended depth-of-field is a fusion algorithm that combines those images into one single sharp composite. One promising method is based on the wavelet transform. Here, we show how the wavelet-based image fusion technique can be improved and easily extended to multichannel data. First, we propose the use of complex-valued wavelet bases, which seem to outperform traditional real-valued wavelet transforms. Second, we introduce a way to apply this technique for multichannel images that suppresses artifacts and does not introduce false colors, an important requirement for multichannel optical microscopy imaging. We evaluate our method on simulated image stacks and give results relevant to biological imaging

PET scan investigations of Huntington's disease: Cerebral metabolic correlates of neurological features and functional decline

Fifteen drug-free patients with early to midstage Huntington's disease were evaluated with quantitative neurological examinations, scales for functional capacity, computed tomographic (CT) scans, and positron emission tomographic (PET) scans of 18 F-2-fluoro-2-deoxyglucose ( 18 F-FDG) uptake. All patients had abnormal indices of caudate metabolism on PET scanning, whereas in patients with early disease indices of putamen metabolism and CT measures of caudate atrophy were normal. Indices of caudate metabolism correlated highly with the patients' overall functional capacity ( r = 0.906; p < 0.001) and bradykinesia/rigidity ( r = −0.692; p < 0.01). Indices of putamen metabolism correlated highly with motor functions: Chorea ( r = −0.841; p < 0.01), oculomotor abnormalities ( r = −0.849; p < 0.01), and fine motor coordination ( r = −0.866; p < 0.01). Indices of thalamic metabolism correlated positively with dystonia ( r = 0.559; p < 0.05). The data suggest that PET scanning with 18 F-FDG is a sensitive measure of brain dysfunction in Huntington's disease and that basal ganglia metabolism is highly correlated with the overall functional capacity of individual patients and with the degree of their motor abnormalities.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/50317/1/410200305_ftp.pd

Preventing Translational Scientists From Extinction: The Long-Term Impact of a Personalized Training Program in Translational Medicine on the Careers of Translational Scientists

Far too much biomedical research is wasted and ends in the so called “Valley of Death”: the gap that exists between biomedical research and its clinical application. While the translational process requires collaboration between many disciplines, current translational medicine focuses on single disciplines. Therefore, educational pathways that integrate clinical and research skills in interdisciplinary and interprofessional contexts are needed. The Eureka institute (http://www.eurekainstitute.org/) was founded to address these issues. The institute organizes an annual 1-week international certificate course to educate professionals in the domains of translational medicine.Study design: This study set out to investigate the impact of the Eureka certificate course on the alumni, focusing on their ability to engage in translational activities and thus become more proficient translational professionals. An explanatory, mixed-methods study was executed.Data collection: A questionnaire was distributed to collect quantitative data on the number of alumni who were able to apply what they learned during the Eureka course and engage in translational activities. Questionnaire data were also used to inform the semi-structured interviews that were conducted subsequently.Results: Fifty-one percent of the alumni reported that participating in the Eureka course played a role in their decision to change to a different job or in the way they were accomplishing their everyday work. Ten conditions for change that either hampered or supported the Eureka alumni's engagement in translational research activities were identified. Further, the learning outcomes of the Eureka course that impacted the alumni's professional activities were explored using Personal Professional Theory (PPT). The insight that alumni gained in the full translational spectrum and stakeholders involved stimulated reflection on their own role within that pathway. Further, according to the alumni, the course provided them with the skills and confidence to pursue a career as translational professional. These learning outcomes, in combination with conditions that supported alumni's engagement in translational activities, such as supportive professional partners, opportunities to network or collaborate, and a translational work environment, contributed to the large number of alumni that were able to engage in translational activities

A bifurcated plantaris muscle: another confirmation of its high morphological variability? Another type of plantaris muscle

The plantaris muscle usually begins with a short, narrow belly in the popliteal fossa at the lateral supracondylar line of the femur and the knee joint capsule. Then it forms a long and slender tendon and usually inserts into the calcaneal tuberosity on the medial side of Achilles tendon. Nevertheless, many anatomical variations of distal attachment have been described. Cases of atypical proximal origin are reported less frequently. In this paper, we have presented a case of a two headed plantaris muscle. First head attached to the condyle of the femoral bone, medially and inferiorly to the lateral head of the gastrocnemius muscle. The second one originated from the popliteal surface of the femur, just above the intercondylar fossa. According to present literature, no such case with atypical proximal origin was presented. Such information has potentially clinical significance during the surgical procedures performed in the area of the popliteal fossa

Local modes, phonons, and mass transport in solid 4^4He

We propose a model to treat the local motion of atoms in solid $^{4}$He as a local mode. In this model, the solid is assumed to be described by the Self Consistent Harmonic approximation, combined with an array of local modes. We show that in the bcc phase the atomic local motion is highly directional and correlated, while in the hcp phase there is no such correlation. The correlated motion in the bcc phase leads to a strong hybridization of the local modes with the T$_{1}(110)$ phonon branch, which becomes much softer than that obtained through a Self Consistent Harmonic calculation, in agreement with experiment. In addition we predict a high energy excitation branch which is important for self-diffusion. Both the hybridization and the presence of a high energy branch are a consequence of the correlation, and appear only in the bcc phase. We suggest that the local modes can play the role in mass transport usually attributed to point defects (vacancies). Our approach offers a more overall consistent picture than obtained using vacancies as the predominant point defect. In particular, we show that our approach resolves the long standing controversy regarding the contribution of point defects to the specific heat of solid $^{4}$He.Comment: 10 pages, 10 figure

IND-Enabling Studies for a Clinical Trial to Genetically Program a Persistent Cancer-Targeted Immune System

PURPOSE: To improve persistence of adoptively transferred T-cell receptor (TCR)-engineered T cells and durable clinical responses, we designed a clinical trial to transplant genetically-modified hematopoietic stem cells (HSCs) together with adoptive cell transfer of T cells both engineered to express an NY-ESO-1 TCR. Here, we report the preclinical studies performed to enable an investigational new drug (IND) application. EXPERIMENTAL DESIGN: HSCs transduced with a lentiviral vector expressing NY-ESO-1 TCR and the PET reporter/suicide gene HSV1-sr39TK and T cells transduced with a retroviral vector expressing NY-ESO-1 TCR were coadministered to myelodepleted HLA-A2/Kb mice within a formal Good Laboratory Practice (GLP)-compliant study to demonstrate safety, persistence, and HSC differentiation into all blood lineages. Non-GLP experiments included assessment of transgene immunogenicity and in vitro viral insertion safety studies. Furthermore, Good Manufacturing Practice (GMP)-compliant cell production qualification runs were performed to establish the manufacturing protocols for clinical use. RESULTS: TCR genetically modified and ex vivo-cultured HSCs differentiated into all blood subsets in vivo after HSC transplantation, and coadministration of TCR-transduced T cells did not result in increased toxicity. The expression of NY-ESO-1 TCR and sr39TK transgenes did not have a detrimental effect on gene-modified HSC's differentiation to all blood cell lineages. There was no evidence of genotoxicity induced by the lentiviral vector. GMP batches of clinical-grade transgenic cells produced during qualification runs had adequate stability and functionality. CONCLUSIONS: Coadministration of HSCs and T cells expressing an NY-ESO-1 TCR is safe in preclinical models. The results presented in this article led to the FDA approval of IND 17471

Comparing phoneme frequency, age of acquisition, and loss in aphasia:Implications for phonological universals

Phonological complexity may be central to the nature of human language. It may shape the distribution of phonemes and phoneme sequences within languages, but also determine age of acquisition and susceptibility to loss in aphasia. We evaluated this claim using frequency statistics derived from a corpus of phonologically transcribed Italian words (phonitalia, available at phonitalia,org), rankings of phoneme age of acquisition (AoA) and rate of phoneme errors in patients with apraxia of speech (AoS) as an indication of articulatory complexity. These measures were related to cross-linguistically derived markedness rankings. We found strong correspondences. AoA, however, was predicted by both apraxic errors and frequency, suggesting independent contributions of these variables. Our results support the reality of universal principles of complexity. In addition they suggest that these complexity principles have articulatory underpinnings since they modulate the production of patients with AoS, but not the production of patients with more central phonological difficulties